This is an Acute Lung Injury SCCOR application designed to study the pathogenesis and treatment of early acute lung injury. Although considerable progress has been made in selected areas of research and treatment of clinical acute lung injury, the pathogenesis of clinical lung injury is incompletely understood and mortality remains too high. Clinical and basic research is needed to provide new knowledge regarding fundamental mechanisms of lung injury as well as to test new therapies for acute lung injury (ALl), an important cause of acute respiratory failure in critically ill patients. Project 1 proposes a randomized, double-blind, phase II clinical trial to evaluate the potential efficacy of activated protein C (APC) for the treatment of acute lung injury. This project will also explore mechanistically the contribution of coagulation and inflammation dependent mechanisms to clinical lung injury. Project 2 is a clinical project to investigate the interactions among human genetics, bacterial genetics, and host events in the development of acute lung injury from bacterial pneumonia. This project will test the potential contribution of Mannose Binding Lectin genetic abnormalities as a cause of severe pneumonia and acute lung injury. This project will also test the hypothesis that P.aeruginosa colonization transforms to lung infection (ventilator-associated pneumonia) when the P.aeruginosa strains express type III virulence genes. Project 3 will examine the contribution of coagulation dependent mechanisms in experimental lung injury in mice by studying genetically modified mice as well as testing the impact of recombinant mouse AP C as therapy for experimental lung injury. Project 4 will examine the role of transforming growth factor-beta1 as a pathogenetic mechanism for early experimental acute lung injury, evaluating the mechanisms for TGF-beta1 activation, and also will identify the mechanisms for responsible for the TGF-beta1 induced alterations in alveolar epithelial fluid transport. The administrative and clinical cores (Cores A & B) will support the scientific objective of the projects. The proteomics core (Core C) will provide innovative methods for identifying novel proteins in the bronchoalveolar lavage fluid from patients and animals with acute lung injury, both before and after several treatment strategies.